Controlled release hydrocodone formulations

ABSTRACT

A solid oral controlled-release dosage form of hydrocodone is disclosed, the dosage form comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and controlled release material.

This application claims the benefit of U.S. Provisional Application No.60/244,424, filed Oct. 30, 2000, which is hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention is directed to hydrocodone formulations exhibitinga therapeutic effect for at least about 24 hours or more whenadministered to a human patient.

BACKGROUND OF THE INVENTION

Once-a-day sustained release opioid formulations are disclosed in U.S.Pat. Nos. 5,478,577; 5,672,360; 5,958,459; 6,103,261; 6,143,332;5,965,161; 5,958,452 and 5,968,551. All documents cited herein,including the foregoing, are incorporated by reference in theirentireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to substantially improve theefficiency and quality of pain management in human patients experiencingmoderate pain.

It is an object of certain embodiments of the present invention toprovide bioavailable hydrocodone formulations suitable for once dailyadministration which substantially improve the efficiency and quality ofpain management.

It is an object of certain embodiments of the present invention toprovide bioavailable controlled-release hydrocodone formulationssuitable for once daily administration which provide a substantiallyincreased duration of effect as compared to immediate releasehydrocodone formulations.

It is an object of certain embodiments of the invention to provideorally administrable controlled release opioid formulations suitable foronce-a-day administration which provide an early onset of therapeuticeffect and which, after rising to a maximum concentration during thedosage interval, provide a relatively flat serum plasma profile, meaningthat the plasma level of the opioid provides a C₂₄/C_(max) ratio ofabout 0.55 to about 1.0, and which provides effective pain relief to thepatient.

The above objects and others are attained by virtue of the presentinvention, which in certain embodiments, provides a solid oralcontrolled-release dosage form comprising an analgesically effectiveamount of hydrocodone or a pharmaceutically acceptable salt thereof anda sufficient amount of a controlled release material to render thedosage form suitable for once-a-day administration, the dosage formafter administration to a human patient or a population of patientsproviding a time to peak plasma concentration of hydrocodone in-vivopreferably from about 4 to about 14 hours (T_(max)), and providing aC₂₄/C_(max) ratio of 0.55 to 1.0.

In certain embodiments of the invention, the dosage form provides a timeto maximum plasma concentration (T_(max)) of hydrocodone in-vivo atabout 6 to about 12 hours, at about 8 to about 10 hours, at about 4 toabout 10 hours or at about 8 to about 14 hours after administration ofthe dosage form.

In certain embodiments of the invention, the dosage form provides aC₂₄/C_(max) ratio of 0.55 to 1.0, of 0.55 to about 0.85, of 0.55 to 0.75or of 0.60 to about 0.70.

In certain preferred embodiments, the controlled release dosage formprovides an in-vitro release when measured by the USP Basket Method at100 rpm in 700 ml Simulated Gastric Fluid (SGF) at 37° C. for 1 hour andthereafter switching to 900 ml with Phosphate Buffer to a pH of 7.5 at37° C., of at least 20% by weight hydrocodone or salt thereof releasedat 4 hrs, from about 20% to about 65% by weight hydrocodone or saltthereof released at 8 hrs, from about 45% to about 85% by weighthydrocodone or salt thereof released at 12 hrs, and at least 80% byweight hydrocodone or salt thereof released at 24 hours. Although thein-vitro release rate may be either pH-independent or pH-dependent asdesired, in preferred embodiments of the invention the release ofhydrocodone is pH-independent.

In certain preferred embodiments, the controlled release dosage formprovides an in-vitro release of the hydrocodone when measured by the USPBasket method at 100 rpm in 700 ml aqueous buffer at a pH of 1.2 at 37°C. of from 10% to about 45% by weight hydrocodone or salt thereofreleased at 1 hour.

In certain embodiments of the invention, the dosage form provides anin-vitro release rate, of hydrocodone or a pharmaceutically acceptablesalt thereof, when measured by the USP Basket Method at 100 rpm in 900ml aqueous buffer at a pH of between 1.6 and 7.2 at 37° C. of from 0% toabout 35% at 1 hour, from about 10% to about 70% at 4 hours, from about20% to about 75% at 8 hours, from about 30% to about 80% at 12 hours,from about 40% to about 90% at 18 hours, and greater than about 60% at24 hours; the in-vitro release rate being substantially independent ofpH in that a difference, at any given time, between an amount of opioidreleased at one pH and an amount released at any other pH, when measuredin-vitro using the USP Paddle Method of U.S. Pharmacopeia XXII (1990) at100 rpm in 900 ml aqueous buffer, is no greater than 10%.

In certain preferred embodiments the sustained release oral dosage formof the present invention provides hydrocodone plasma levels which areeffective for 24 hourly dosing, characterized by a W₅₀ for thehydrocodone of between 4 and 22 hours. In certain embodiments, the W₅₀is at least 4 hours, preferably at least 12 hours, and more preferablyat least 18 hours.

In certain embodiments the sustained release oral dosage form of thepresent invention comprises a matrix which includes a sustained releasematerial and hydrocodone or a pharmaceutically acceptable salt thereof.In certain embodiments, the matrix is compressed into a tablet and maybe optionally overcoated with a coating that in addition to thesustained release material of the matrix may control the release of thehydrocodone or pharmaceutically acceptable salt thereof from theformulation, such that blood levels of active ingredient are maintainedwithin the therapeutic range over an extended period of time. In certainalternate embodiments, the matrix is encapsulated.

In certain embodiments, the sustained release oral dosage form of thepresent invention comprises a plurality of pharmaceutically acceptablesustained release matrices comprising hydrocodone or a pharmaceuticallyacceptable salt thereof, the dosage form maintaining the blood plasmalevels of hydrocodone within the therapeutic range over an extendedperiod of time when administered to patients.

In certain embodiments the sustained release oral dosage form of thepresent invention is an osmotic dosage form which comprises a singlelayer or bilayer core comprising hydrocodone or a pharmaceuticallyacceptable salt thereof; an expandable polymer; a semipermeable membranesurrounding the core; and a passageway disposed in the semipermeablemembrane for sustained release of the hydrocodone or pharmaceuticallyacceptable salt thereof, such that blood levels of active ingredient aremaintained within the therapeutic range over an extended period of timewhen administered to patients.

In certain preferred embodiments of the invention, there is provided aonce-a-day oral controlled release dosage form of hydrocodone whichprovides a C_(max) of hydrocodone which less than about 60%, less thanabout 50% or less than about 40% of the C_(max) of an equivalent dose ofan immediate release hydrocodone reference formulation (e.g. Lortab®),and which provides effective analgesia during the 24 hour dosageinterval.

In certain preferred embodiments of the invention, there is provided aonce-a-day oral controlled release hydrocodone dosage form whichprovides a rate of absorption during the time period from T_(max) toabout 24 hours after oral administration of the dosage form which isfrom about 45% to about 85% of the rate of elimination during the sametime period.

In certain preferred embodiments the dosage form of the presentinvention provides a therapeutic effect for at least about 24 hoursafter administration of the dosage form.

In certain embodiments, any one or all of the above in-vivo parametersare achieved after a first administration of the dosage form to a humanpatient or a population of human patients.

In certain alternative embodiments, any one or all of the above in-vivoparameters are achieved after steady state administration of the dosageform to a human patient or a population of human patients.

“Hydrocodone” is defined for purposes of the invention as includinghydrocodone free base, as well as pharmaceutically acceptable salts andcomplexes of hydrocodone.

The term “USP Paddle or Basket Method” is the Paddle and Basket Methoddescribed, e.g., in U.S. Pharmacopoeia XXII (1990), herein incorporatedby reference.

The term “pH-dependent” for purposes of the present invention is definedas having characteristics (e.g., dissolution) which vary according toenvironmental pH.

The term “pH-independent” for purposes of the present invention isdefined as having characteristics (e.g., dissolution) which aresubstantially unaffected by pH.

The term “bioavailability” is defined for purposes of the presentinvention as the extent to which the drug (e.g., hydrocodone) isabsorbed from the unit dosage forms.

The term “controlled-release” is defined for purposes of the presentinvention as the release of the drug (e.g., hydrocodone) at such a ratethat blood (e.g., plasma) concentrations are maintained within thetherapeutic range but below toxic concentrations over a period of timeof about 12 hours or longer.

The term “C_(max)” denotes the maximum plasma concentration obtainedduring the dosing interval.

The term “C₂₄” as it is used herein is the plasma concentration of thedrug at 24 hours after administration.

The term “T_(max)” denotes the time to maximum plasma concentration(Cmax).

The term “W₅₀” for purposes of the present invention is the durationover which the plasma concentrations are equal to or greater than 50% ofthe peak concentration.

The term “C₂₄/C_(max) ratio” is defined for purposes of the presentinvention as the ratio of the plasma concentration of the drug at 24hours after administration to the highest plasma concentration of thedrug attained within the dosing interval.

The term “semipermeable wall” for purposes of the present inventionmeans that the wall is permeable to the passage of an exterior fluid,such as aqueous or biological fluid, in the environment of use,including the gastrointestinal tract, but impermeable to drug.

The term “minimum effective analgesic concentration” or “MEAC” withrespect to concentrations of opioids such as hydrocodone is verydifficult to quantify. However, there is generally a minimally effectiveanalgesic concentration of plasma hydrocodone below which no analgesiais provided. While there is an indirect relationship between, e.g.,plasma hydrocodone levels and analgesia, higher and prolonged plasmalevels are generally associated with superior pain relief. There is alag time or hysteresis, between the time of peak plasmahydrocodone-levels and the time of peak drug effects. This holds truefor the treatment of pain with opioid analgesics in general.

For purposes of the invention, unless further specified, the term “apatient” means that the discussion (or claim) is directed to thepharmacokinetic parameters of an individual patient or subject.

The term “population of patients” means that the discussion (or claim)is directed to the mean pharmacokinetic parameters of at least twopatients or subjects.

The term “immediate release hydrocodone reference formulation” forpurposes of the present invention, is an equivalent amount of thehydrocodone portion of Lortab®, commercially available from UCB Pharma,Inc, or a pharmaceutical product that provides an immediate release ofhydrocodone or a salt thereof.

For purposes of the invention, the controlled release formulationsdisclosed herein and the immediate release control formulations are doseproportional. In such formulations, the pharmacokinetic parameters(e.g., AUC and C_(max)) increase linearly from one dosage strength toanother. Therefore the pharmacokinetic parameters of a particular dosecan be inferred from the parameters of a different dose of the sameformulation.

The term “first administration” means a single dose of the presentinvention at the initiation of therapy to an individual patient or apatient population.

The term “steady state” means that the amount of the drug reaching thesystem is approximately the same as the amount of the drug leaving thesystem. Thus, at “steady-state”, the patient's body eliminates the drugat approximately the same rate that the drug becomes available to thepatient's system through absorption into the blood stream.

The controlled-release oral solid dosage forms of the present inventionmay be opioid-sparing. It is possible that the controlled-release oralsolid dosage forms of the present invention may be dosed at asubstantially lower daily dosage in comparison to conventionalimmediate-release products, with no difference in analgesic efficacy. Atcomparable daily dosages, greater efficacy may result with the use ofthe controlled-release oral solid dosage forms of the present inventionin comparison to conventional immediate-release products.

DETAILED DESCRIPTION

The above embodiments of the invention can be provided by modifying awide variety of controlled release formulations known to those skilledin the art. For example, the materials and methods disclosed in U.S.Pat. Nos. 4,861,598, 4,970,075, 5,958,452, and 5,965,161 can be modifiedto prepare the present invention. These references are herebyincorporated by reference.

Active Agent

The controlled release oral dosage forms of the present inventionpreferably include from about 0.5 mg to about 1250 mg hydrocodone or anequivalent amount of a pharmaceutically acceptable salt thereof. Morepreferably, the dosage form contains from about 5 to about 60 mg (e.g.30 mg) hydrocodone or salt thereof. Suitable pharmaceutically acceptablesalts of hydrocodone include hydrocodone bitartrate, hydrocodonebitartrate hydrate, hydrocodone hydrochloride, hydrocodonep-toluenesulfonate, hydrocodone phosphate, hydrocodonethiosemicarbazone, hydrocodone sulfate, hydrocodone trifluoroacetate,hydrocodone hemipentahydrate, hydrocodone pentafluoropropionate,hydrocodone p-nitrophenylhydrazone, hydrocodone o-methyloxime,hydrocodone semicarbazone, hydrocodone hydrobromide, hydrocodone mucate,hydrocodone oleate, hydrocodone phosphate dibasic, hydrocodone phosphatemonobasic, hydrocodone inorganic salt, hydrocodone organic salt,hydrocodone acetate trihydrate, hydrocodone bis(heptafuorobutyrate),hydrocodone bis(methylcarbamate), hydrocodonebis(pentafluoropropionate), hydrocodone bis(pyridine carboxylate),hydrocodone bis(trifluoroacetate), hydrocodone chlorhydrate, andhydrocodone sulfate pentahydrate. Preferably, the hydrocodone is presentas the bitartrate salt.

The dosage forms of the present invention may further include one ormore additional drugs which may or may not act synergistically with thehydrocodone analgesics of the present invention. Examples of suchadditional drugs include non-steroidal anti-inflammatory agents,including ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen,fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen,oxaprozin, pramoprofen, muroprofen, trioxapro-fen, suprofen,aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin,sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin,fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid,flufenamic acid, niflumic acid tolfenamic acid, diflurisal, flufenisal,piroxicam, sudoxicam or isoxicam, and the like. Such non-steroidalanti-inflammatory agents also include cyclo-oxygenase inhibitors such ascelecoxib (SC-58635), DUP-697, flosulide (CGP-28238), meloxicam,6-methoxy-2 naphthylacetic acid (6-MNA), Vioxx (MK-966), nabumetone(prodrug for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, and T-614.as amantadine (1-aminoadamantine), and memantine (3,5dimethylaminoadamantone), their mixtures and pharmaceutically acceptablesalts thereof.

Other additional drugs include nontoxic NMDA receptor antagonists suchdextrorphan, dextromethorphan,3-(1-naphthalennyl)-5-(phosphonomethyl)-L-phenylalanine,3-(1-naphthalenyl)-5-(phosphonomethyl)-DL-phenylalanine,1-(3,5-dimethylphenyl)naphthalene, and2-(3,5-dimethylphenyl)naphthalene,2SR,4RS-4-(((1H-Tetrazol-5-yl)methyl)oxy)piperidine-2-carboxylic acid;2SR,4RS-4-((((1H-Tetrazol-5-yl)methyl)oxy)methyl)piperidine-2-carboxylicacid; E and Z2SR-4-(O-(1H-Tetrazol-5-yl)methyl)ketoximino)piperidine-2-carboxylicacid; 2SR,4RS-4-((1H-Tetrazol-5-yl)thio)piperidine-2-carboxylic acid;2SR,4RS-4-((1H-Tetrazol-5-yl)thio)piperidine-2-carboxylic acid;2SR,4RS-4-(5-mercapto-1H-Tetrazol-1-yl)piperidine-2-carboxylic acid;2SR,4RS-4-(5-mercapto-2H-Tetrazol-2-yl)piperidine-2-carboxylic acid;2SR,4RS-4-(5-mercapto-1H-Tetrazol-1-yl)piperidine-2-carboxylic acid;2SR,4RS-4-(5-mercapto-2H-Tetrazol-2-yl)piperidine-2-carboxylic acid;2SR,4RS-4-(((1H-Tetrazol-5-yl)thio)methyl)piperidine-2-carboxylic acid;2SR,4RS-4-((5-mercapto-1H-Tetrazol-1-yl)methyl)piperidine-2-carboxylicacid; or2SR,4RS-4-((5-mercapto-2H-Tetrazol-2-yl)methyl)piperidine-2-carboxylicacid, their mixtures and pharmaceutically acceptable salts thereof.

Other suitable additional drugs which may be included in the dosageforms of the present invention include acetaminophen, aspirin,neuro-active steroids (such as those disclosed in U.S. Ser. No.09/026,520, filed Feb. 20, 1998, hereby incorporated by reference) andother non-opioid analgesics.

For example, if a second (non-opioid) drug is included in theformulation, such drug may be included in controlled release form or inimmediate release form. The additional drug may be incorporated into thecontrolled release matrix along with the opioid; incorporated into thecontrolled release coating; incorporated as a separated controlledrelease layer or immediate release layer; or may be incorporated as apowder, granulation, etc., in a gelatin capsule with the substrates ofthe present invention.

In certain preferred embodiments of the present invention, an effectiveamount of hydrocodone in immediate release form is included in thecontrolled release unit dose hydrocodone formulation to be administered.The immediate release form of the hydrocodone is preferably included inan amount which is effective to shorten the time to C_(max) of thehydrocodone in the blood (e.g., plasma). The immediate release form ofthe opioid is preferably included in an amount which is effective toshorten the time to maximum concentration of the opioid in the blood(e.g., plasma), such that the T_(max) is shortened to a time of, e.g.,from about 4 to about 10 hours, or from about 6 to about 8 hours. Insuch embodiments, an effective amount of the hydrocodone in immediaterelease form may be coated onto the substrates of the present invention.For example, where the extended release hydrocodone from the formulationis due to a controlled release coating, the immediate release layerwould be overcoated on top of the controlled release coating. On theother hand, the immediate release layer may be coated onto the surfaceof substrates wherein the hydrocodone is incorporated in a controlledrelease matrix. Where a plurality of the sustained release substratescomprising an effective unit dose of the hydrocodone (e.g.,multiparticulate systems including pellets, spheres, beads and the like)are incorporated into a hard gelatin capsule, the immediate releaseportion of the opioid dose may be incorporated into the gelatin capsulevia inclusion of the sufficient amount of immediate release hydrocodoneas a powder or granulate within the capsule. Alternatively, the gelatincapsule itself may be coated with an immediate release layer of thehydrocodone. One skilled in the art would recognize still otheralternative manners of incorporating the immediate release hydromorphoneportion into the unit dose. Such alternatives are deemed to beencompassed by the appended claims. By including such an effectiveamount of immediate release hydrocodone in the unit dose, the experienceof relatively higher levels of pain in patients may be significantlyreduced.

Dosage Forms

The controlled-release dosage form may optionally include a controlledrelease material which is incorporated into a matrix along with thehydrocodone, or which is applied as a sustained release coating over asubstrate comprising the drug (the term “substrate” encompassing beads,pellets, spheroids, tablets, tablet cores, etc). The controlled releasematerial may be hydrophobic or hydrophilic as desired. The oral dosageform according to the invention may be provided as, for example,granules, spheroids, pellets or other multiparticulate formulations. Anamount of the multiparticulates which is effective to provide thedesired dose of opioid over time may be placed in a capsule or may beincorporated in any other suitable oral solid form, e.g., compressedinto a tablet. On the other hand, the oral dosage form according to thepresent invention may be prepared as a tablet core coated with acontrolled-release coating, or as a tablet comprising a matrix of drugand controlled release material, and optionally other pharmaceuticallydesirable ingredients (e.g., diluents, binders, colorants, lubricants,etc.). The controlled release dosage form of the present invention mayalso be prepared as a bead formulation or an osmotic dosage formulation.

Controlled Release Matrix Formulations

In certain preferred embodiments of the present invention, thecontrolled-release formulation is achieved via a matrix (e.g. a matrixtablet) which includes a controlled-release material as set forth below.A dosage form including a controlled-release matrix provides in-vitrodissolution rates of the opioid within the preferred ranges and thatreleases the opioid in a pH-dependent or pH-independent manner. Thematerials suitable for inclusion in a controlled-release matrix willdepend on the method used to form the matrix. The oral dosage form maycontain between 1% and 80% (by weight) of at least one hydrophilic orhydrophobic controlled release material.

A non-limiting list of suitable controlled-release materials which maybe included in a controlled-release matrix according to the inventioninclude hydrophilic and/or hydrophobic materials, such as gums,cellulose ethers, acrylic resins, protein derived materials, waxes,shellac, and oils such as hydrogenated castor oil, hydrogenatedvegetable oil. However, any pharmaceutically acceptable hydrophobic orhydrophilic controlled-release material which is capable of impartingcontrolled-release of the opioid may be used in accordance with thepresent invention. Preferred controlled-release polymers includealkylcelluloses such as ethylcellulose, acrylic and methacrylic acidpolymers and copolymers, and cellulose ethers, especiallyhydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose) andcarboxyalkylcelluloses. Preferred acrylic and methacrylic acid polymersand copolymers include methyl methacrylate, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate,aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylicacid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate),poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.Certain preferred embodiments utilize mixtures of any of the foregoingcontrolled-release materials in the matrices of the invention.

The matrix also may include a binder. In such embodiments, the binderpreferably contributes to the controlled-release of the hydrocodone fromthe controlled-release matrix.

Preferred hydrophobic binder materials are water-insoluble with more orless pronounced hydrophilic and/or hydrophobic trends. Preferredhydrophobic binder materials which may be used in accordance with thepresent invention include digestible, long chain (C₈-C₅₀, especiallyC₁₂-C₄₀), substituted or unsubstituted hydrocarbons, such as fattyacids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils, natural and synthetic waxes and polyalkylene glycols.Preferably, the hydrophobic binder materials useful in the inventionhave a melting point from about 30 to about 200° C., preferably fromabout 45 to about 90° C. When the hydrophobic material is a hydrocarbon,the hydrocarbon preferably has a melting point of between 25° and 90° C.Of the long chain (C₈-C₅₀) hydrocarbon materials, fatty (aliphatic)alcohols are preferred. The oral dosage form may contain up to 80% (byweight) of at least one digestible, long chain hydrocarbon.

Preferably, the oral dosage form contains up to 80% (by weight) of atleast one polyalkylene glycol. The hydrophobic binder material maycomprise natural or synthetic waxes, fatty alcohols (such as lauryl,myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fattyacids, including but not limited to fatty acid esters, fatty acidglycerides (mono-, di-, and tri-glycerides), hydrogenated fats,hydrocarbons, normal waxes, stearic acid, stearyl alcohol andhydrophobic and hydrophilic materials having hydrocarbon backbones.Suitable waxes include, for example, beeswax, glycowax, castor wax andcarnauba wax. For purposes of the present invention, a wax-likesubstance is defined as any material which is normally solid at roomtemperature and has a melting point of from about 30 to about 100° C.

In certain preferred embodiments, a combination of two or morehydrophobic binder materials are included in the matrix formulations. Ifan additional hydrophobic binder material is included, it is preferablyselected from natural and synthetic waxes, fatty acids, fatty alcohols,and mixtures of the same. Examples include beeswax, carnauba wax,stearic acid and stearyl alcohol. This list is not meant to beexclusive.

One particular suitable controlled-release matrix comprises at least onewater soluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferablyC₁₄-C₂₂, aliphatic alcohol and, optionally, at least one polyalkyleneglycol. The hydroxyalkyl cellulose is preferably a hydroxy (C₁ to C₆)alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose.The amount of the at least one hydroxyalkyl cellulose in the presentoral dosage form will be determined, inter alia, by the precise rate ofopioid release required. The aliphatic alcohol may be, for example,lauryl alcohol, myristyl alcohol or stearyl alcohol. In particularlypreferred embodiments of the present oral dosage form, however, the atleast one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. Theamount of the aliphatic alcohol in the present oral dosage form will bedetermined, as above, by the precise rate of opioid release required. Itwill also depend on whether at least one polyalkylene glycol is presentin or absent from the oral dosage form. In the absence of at least onepolyalkylene glycol, the oral dosage form preferably contains between20% and 50% (by wt) of the aliphatic alcohol. When a polyalkylene glycolis present in the oral dosage form, then the combined weight of thealiphatic alcohol and the polyalkylene glycol preferably constitutesbetween 20% and 50% (by wt) of the total dosage.

In one preferred embodiment, the ratio of, e.g., the at least onehydroxyalkyl cellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a consider-able extent, therelease rate of the opioid from the formulation. A ratio of thehydroxyalkyl cellulose to the aliphatic alcohol/polyalkylene glycol ofbetween 1:2 and 1:4 is preferred, with a ratio of between 1:3 and 1:4being particularly preferred.

The polyalkylene glycol may be, for example, polypropylene glycol or,which is preferred, polyethylene glycol. The number average molecularweight of the at least one polyalkylene glycol is preferred between1,000 and 15,000 especially between 1,500 and 12,000.

Another suitable controlled-release matrix comprises an alkylcellulose(especially ethylcellulose), a C₁₂ to C₃₆ aliphatic alcohol and,optionally, a polyalkylene glycol.

In addition to the above ingredients, a controlled-release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

In order to facilitate the preparation of a solid, controlled-releaseoral dosage form according to this invention there is provided, in afurther aspect of the present invention, a process for the preparationof a solid, controlled-release oral dosage form according to the presentinvention comprising incorporating opioids or a salt thereof in acontrolled-release matrix. Incorporation in the matrix may be effected,for example, by

(a) forming granules comprising at least one hydrophobic and/orhydrophilic material as set forth above (e.g., a water solublehydroxyalkyl cellulose) together with the hydrocodone;

(b) mixing the at least one hydrophobic and/or hydrophilicmaterial-containing granules with at least one C₁₂-C₃₆ aliphaticalcohol, and

(c) optionally, compressing and shaping the granules.

The granules may be formed by any of the procedures well-known to thoseskilled in the art of pharmaceutical formulation. For example, in onepreferred method, the granules may be formed by wet granulatinghydroxyalkyl cellulose/opioid with water. In a particularly preferredembodiment of this process, the amount of water added during the wetgranulation step is preferably between 1.5 and 5 times, especiallybetween 1.75 and 3.5 times, the dry weight of the opioid.

In certain embodiments, the dosage form comprises a plurality ofmatrices described above.

The matrices of the present invention may also be prepared via a meltpellitization technique. In such circumstance, the opioid in finelydivided form is combined with a binder (also in particulate form) andother optional inert ingredients, and thereafter the mixture ispelletized, e.g., by mechanically working the mixture in a high shearmixer to form the pellets (granules, spheres). Thereafter, the pellets(granules, spheres) may be sieved in order to obtain pellets of therequisite size. The binder material is preferably in particulate formand has a melting point above about 40° C. Suitable binder substancesinclude, for example, hydrogenated castor oil, hydrogenated vegetableoil, other hydrogenated fats, fatty alcohols, fatty acid esters, fattyacid glycerides, and the like.

Controlled-release matrices can also be prepared by, e.g.,melt-granulation or melt-extrusion techniques. Generally,melt-granulation techniques involve melting a normally solid hydrophobicbinder material, e.g. a wax, and incorporating a powdered drug therein.To obtain a controlled release dosage form, it may be necessary toincorporate a hydrophobic controlled release material, e.g.ethylcellulose or a water-insoluble acrylic polymer, into the molten waxhydrophobic binder material. Examples of controlled-release formulationsprepared via melt-granulation techniques are found, e.g., in U.S. Pat.No. 4,861,598, assigned to the Assignee of the present invention andhereby incorporated by reference in its entirety.

The hydrophobic binder material may comprise one or more water-insolublewax-like thermoplastic substances possibly mixed with one or morewax-like thermoplastic substances being less hydrophobic than said oneor more water-insoluble wax-like substances. In order to achievecontrolled release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like binder substances may be those with awater-solubility that is lower than about 1:5,000 (w/w).

In addition to the above ingredients, a controlled release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art in amounts upto about 50% by weight of the particulate if desired. The quantities ofthese additional materials will be sufficient to provide the desiredeffect to the desired formulation.

The preparation of a suitable melt-extruded matrix according to thepresent invention may, for example, include the steps of blending theopioid analgesic, together with a controlled release material andpreferably a binder material to obtain a homogeneous mixture. Thehomogeneous mixture is then heated to a temperature sufficient to atleast soften the mixture sufficiently to extrude the same. The resultinghomogeneous mixture is then extruded, e.g., using a twin-screw extruder,to form strands. The extrudate is preferably cooled and cut intomultiparticulates by any means known in the art. The strands are cooledand cut into multiparticulates. The multiparticulates are then dividedinto unit doses. The extrudate preferably has a diameter of from about0.1 to about 5 mm and provides controlled release of the therapeuticallyactive agent for a time period of from about 8 to at least about 24hours.

An optional process for preparing the melt extrusioned formulations ofthe present invention includes directly metering into an extruder ahydrophobic controlled release material, a therapeutically active agent,and an optional binder material; heating the homogenous mixture;extruding the homogenous mixture to thereby form strands; cooling thestrands containing the homogeneous mixture; cutting the strands intoparticles having a size from about 0.1 mm to about 12 mm; and dividingsaid particles into unit doses. In this aspect of the invention, arelatively continuous manufacturing procedure is realized.

Plasticizers, such as those described herein, may be included inmelt-extruded matrices. The plasticizer is preferably included as fromabout 0.1 to about 30% by weight of the matrix. Other pharmaceuticalexcipients, e.g., talc, mono or poly saccharides, colorants, flavorants,lubricants and the like may be included in the controlled releasematrices of the present invention as desired. The amounts included willdepend upon the desired characteristic to be achieved.

The diameter of the extruder aperture or exit port can be adjusted tovary the thickness of the extruded strands. Furthermore, the exit partof the extruder need not be round; it can be oblong, rectangular, etc.The exiting strands can be reduced to particles using a hot wire cutter,guillotine, etc.

A melt extruded multiparticulate system can be, for example, in the formof granules, spheroids or pellets depending upon the extruder exitorifice. For purposes of the present invention, the terms “melt-extrudedmultiparticulate(s)” and “melt-extruded multiparticulate system(s)” and“melt-extruded particles” shall refer to a plurality of units,preferably within a range of similar size and/or shape and containingone or more active agents and one or more excipients, preferablyincluding a hydrophobic controlled release material as described herein.Preferably the melt-extruded multiparticulates will be of a range offrom about 0.1 to about 12 mm in length and have a diameter of fromabout 0.1 to about 5 mm. In addition, it is to be understood that themelt-extruded multiparticulates can be any geometrical shape within thissize range. Alternatively, the extrudate may simply be cut into desiredlengths and divided into unit doses of the therapeutically active agentwithout the need of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared that includean effective amount of melt-extruded multiparticulates within a capsule.For example, a plurality of the melt-extruded multiparticulates may beplaced in a gelatin capsule in an amount sufficient to provide aneffective controlled release dose when ingested and contacted by gastricfluid.

In another preferred embodiment, a suitable amount of themultiparticulate extrudate is compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980),incorporated by reference herein.

In yet another preferred embodiment, the extrudate can be shaped intotablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et. al.),hereby incorporated by reference.

Optionally, the controlled-release matrix multiparticulate systems ortablets can be coated, or the gelatin capsule can be further coated,with a controlled release coating such as the controlled releasecoatings described above. Such coatings preferably include a sufficientamount of hydrophobic and/or hydrophilic controlled-release material toobtain a weight gain level from about 2 to about 25 percent, althoughthe overcoat may be greater depending upon, e.g., the physicalproperties of the particular opioid analgesic used and the desiredrelease rate, among other things.

The dosage forms of the present invention may further includecombinations of melt-extruded multiparticulates containing one or moreopioid analgesics. Furthermore, the dosage forms can also include anamount of an immediate release therapeutically active agent for prompttherapeutic effect. The immediate release therapeutically active agentmay be incorporated, e.g., as separate pellets within a gelatin capsule,or may be coated on the surface of, e.g., melt extrudedmultiparticulates. The unit dosage forms of the present invention mayalso contain a combination of, e.g., controlled release beads and matrixmultiparticulates to achieve a desired effect.

The controlled-release formulations of the present invention preferablyslowly release the therapeutically active agent, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. Thecontrolled-release profile of the melt-extruded formulations of theinvention can be altered, for example, by varying the amount ofcontrolled-release material, by varying the amount of plasticizerrelative to other matrix constituents, hydrophobic material, by theinclusion of additional ingredients or excipients, by altering themethod of manufacture, etc.

In other embodiments of the invention, melt-extruded formulations areprepared without the inclusion of the therapeutically active agent,which is added thereafter to the extrudate Such formulations typicallywill have the therapeutically active agent blended together with theextruded matrix material, and then the mixture would be tableted inorder to provide a slow release formulation. Such formulations may beadvantageous, for example, when the therapeutically active agentincluded in the formulation is sensitive to temperatures needed forsoftening the hydrophobic material and/or the retardant material.

Typical melt-extrusion production systems suitable for use in accordancewith the present invention include a suitable extruder drive motorhaving variable speed and constant torque control, start-stop controls,and ammeter. In addition, the production system will include atemperature control console which includes temperature sensors, coolingmeans and temperature indicators throughout the length of the extruder.In addition, the production system will include an extruder such astwin-screw extruder which consists of two counter-rotating intermeshingscrews enclosed within a cylinder or barrel having an aperture or die atthe exit thereof. The feed materials enter through a feed hopper and aremoved through the barrel by the screws and are forced through the dieinto strands which are thereafter conveyed such as by a continuousmovable belt to allow for cooling and being directed to a pelletizer orother suitable device to render the extruded ropes into themultiparticulate system. The pelletizer can consist of rollers, fixedknife, rotating cutter and the like. Suitable instruments and systemsare available from distributors such as C.W. Brabender Instruments, Inc.of South Hackensack, N.J. Other suitable apparatus will be apparent tothose of ordinary skill in the art.

A further aspect of the invention is related to the preparation ofmelt-extruded multiparticulates as set forth above in a manner whichcontrols the amount of air included in the extruded product. Bycontrolling the amount of air included in the extrudate, the releaserate of the therapeutically active agent from the, e.g.,multiparticulate extrudate, can be altered significantly. In certainembodiments, the pH dependency of the extruded product can be altered aswell.

Thus, in a further aspect of the invention, the melt-extruded product isprepared in a manner which substantially excludes air during theextrusion phase of the process. This may be accomplished, for example,by using a Leistritz extruder having a vacuum attachment. In certainembodiments the extruded multiparticulates prepared according to theinvention using the Leistritz extruder under vacuum provides amelt-extruded product having different physical characteristics. Inparticular, the extrudate is substantially non-porous when magnified,e.g., using a scanning electron microscope which provides an SEM(scanning electron micrograph). Such substantially non-porousformulations provide a faster release of the therapeutically activeagent, relative to the same formulation prepared without vacuum. SEMs ofthe multiparticulates prepared using an extruder under vacuum appearvery smooth, and the multiparticulates tend to be more robust than thosemultiparticulates prepared without vacuum. In certain formulations, theuse of extrusion under vacuum provides an extruded multiparticulateproduct which is more pH-dependent than its counterpart formulationprepared without vacuum. Alternatively, the melt-extruded product isprepared using a Werner-Pfleiderer twin screw extruder.

In certain embodiments, a spheronising agent is added to a granulate ormultiparticulates of the present invention and then spheronized toproduce controlled release spheroids. The spheroids are then optionallyovercoated with a controlled release coating by methods such as thosedescribed herein.

Spheronising agents which may be used to prepare the multiparticulateformulations of the present invention include any art-known spheronisingagent. Cellulose derivatives are preferred, and microcrystallinecellulose is especially preferred. A suitable microcrystalline celluloseis, for example, the material sold as Avicel PH 101 (Trade Mark, FMCCorporation). The spheronising agent is preferably included as about 1to about 99% of the multiparticulate by weight.

In addition to the active ingredient and spheronizing agent, thespheroids may also contain a binder. Suitable binders, such as lowviscosity, water soluble polymers, will be well known to those skilledin the pharmaceutical art. However, water soluble hydroxy loweralkylcellulose, such as hydroxypropylcellulose, are preferred.

In addition to the opioid analgesic and spheronising agent, themultiparticulate formulations of the present invention may include acontrolled release material such as those described hereinabove.Preferred controlled-release materials for inclusion in themultiparticulate formulations include acrylic and methacrylic acidpolymers or copolymers, and ethylcellulose. When present in theformulation, the controlled-release material will be included in amountsof from about 1 to about 80% of the multiparticulate, by weight. Thecontrolled-release material is preferably included in themultiparticulate formulation in an amount effective to providecontrolled release of the opioid analgesic from the multiparticulate.

Pharmaceutical processing aids such as binders, diluents, and the likemay be included in the multiparticulate formulations. Amounts of theseagents included in the formulations will vary with the desired effect tobe exhibited by the formulation.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms of the present inventionare described in the Handbook of Pharmaceutical Excipients, AmericanPharmaceutical Association (1986), incorporated by reference herein.

The multiparticulates may be overcoated with a controlled-releasecoating including a controlled-release material such as those describedhereinabove. The controlled-release coating is applied to a weight gainof from about 5 to about 30%. The amount of the controlled-releasecoating to be applied will vary according to a variety of factors, e.g.,the composition of the multiparticulate and the chemical and/or physicalproperties of the opioid analgesic (i.e., hydrocodone).

Matrix multiparticulates may also be prepared by granulating thespheronising agent together with the opioid analgesic, e.g. by wetgranulation. The granulate is then spheronized to produce the matrixmultiparticulates. The matrix multiparticulates are then optionallyovercoated with the controlled release coating by methods such as thosedescribed hereinabove.

Another method for preparing matrix multiparticulates, for example, by(a) forming granules comprising at least one water soluble hydroxyalkylcellulose and opioid or an opioid salt; (b) mixing the hydroxyalkylcellulose containing granules with at least one C₁₂-C₃₆ aliphaticalcohol; and (c) optionally, compressing and shaping the granules.Preferably, the granules are formed by wet granulating the hydroxyalkylcellulose/opioid with water. In a particularly preferred embodiment ofthis process, the amount of water added during the wet granulation stepis preferably between 1.5 and 5 times, especially between 1.75 and 3.5times, the dry weight of the opioid.

In yet other alternative embodiments, a spheronizing agent, togetherwith the active ingredient can be spheronized to form spheroids.Microcrystalline cellulose is preferred. A suitable microcrystallinecellulose is, for example, the material sold as Avicel PH 101 (TradeMark, FMC Corporation). In such embodiments, in addition to the activeingredient and spheronizing agent, the spheroids may also contain abinder. Suitable binders, such as low viscosity, water soluble polymers,will be well known to those skilled in the pharmaceutical art. However,water soluble hydroxy lower alkyl cellulose, such as hydroxy propylcellulose, are preferred. Additionally (or alternatively) the spheroidsmay contain a water insoluble polymer, especially an acrylic polymer, anacrylic copolymer, such as a methacrylic acid-ethyl acrylate co-polymer,or ethyl cellulose. In such embodiments, the sustained-release coatingwill generally include a water insoluble material such as (a) a wax,either alone or in admixture with a fatty alcohol; or (b) shellac orzein.

Spheroids of the present invention comprise a matrix formulation asdescribed above or bead formulation as described hereinafter having adiameter of between 0.1 mm and 2.5 mm, especially between 0.5 mm and 2mm.

The spheroids are preferably film coated with a controlled releasematerial that permits release of the opioid (or salt) at a controlledrate in an aqueous medium. The film coat is chosen so as to achieve, incombination with the other stated properties, the in-vitro release rateoutlined above (e.g., at least about 12.5% released after 1 hour). Thecontrolled-release coating formulations of the present inventionpreferably produce a strong, continuous film that is smooth and elegant,capable of supporting pigments and other coating additives, non-toxic,inert, and tack-free.

Preparation of Coated Bead Formulations

In certain embodiments of the present invention the oral solidcontrolled release dosage form of the present invention comprises aplurality of coated substrates, e.g., inert pharmaceutical beads such asnu pariel 18/20 beads. An aqueous dispersion of hydrophobic material isused to coat the beads to provide for the controlled release of thehydrocodone. In certain embodiments a plurality of the resultantstabilized solid controlled-release beads may be placed in a gelatincapsule in an amount sufficient to provide an effectivecontrolled-release dose when ingested and contacted by an environmentalfluid, e.g., gastric fluid or dissolution media.

The stabilized controlled-release bead formulations of the presentinvention slowly release the opioid analgesic, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. Thecontrolled-release profile of the formulations of the invention can bealtered, for example, by varying the amount of overcoating with theaqueous dispersion of hydrophobic controlled release material, alteringthe manner in which the plasticizer is added to the aqueous dispersionof hydrophobic controlled release material, by varying the amount ofplasticizer relative to hydrophobic controlled release material, by theinclusion of additional ingredients or excipients, by altering themethod of manufacture, etc. The dissolution profile of the ultimateproduct may also be modified, for example, by increasing or decreasingthe thickness of the controlled release coating.

Substrates coated with a therapeutically active agent are prepared, e.g.by dissolving the therapeutically active agent in water and thenspraying the solution onto a substrate, for example, nu pariel 18/20beads, using a Wuster insert. Optionally, additional ingredients arealso added prior to coating the beads in order to assist the binding ofthe opioid to the beads, and/or to color the solution, etc. For example,a product which includes hydroxypropyl methylcellulose, etc. with orwithout colorant (e.g., Opadry®, commercially available from Colorcon,Inc.) may be added to the solution and the solution mixed (e.g., forabout 1 hour) prior to application of the same onto the substrate. Theresultant coated substrate may then be optionally overcoated with abarrier agent, to separate the therapeutically active agent from thehydrophobic controlled-release coating.

An example of a suitable barrier agent is one which compriseshydroxypropyl methylcellulose. However, any film-former known in the artmay be used. It is preferred that the barrier agent does not affect thedissolution rate of the final product.

The substrates may then be overcoated with an aqueous dispersion of thehydrophobic controlled release material as described herein. The aqueousdispersion of hydrophobic controlled release material preferably furtherincludes an effective amount of plasticizer, e.g. tri-ethyl citrate.Pre-formulated aqueous dispersions of ethylcellulose, such as Aquacoat®or Surelease®, may be used. If Surelease® is used, it is not necessaryto separately add a plasticizer. Alternatively, pre-formulated aqueousdispersions of acrylic polymers such as Eudragit® can be used.

The coating solutions of the present invention preferably contain, inaddition to the film-former, plasticizer, and solvent system (i.e.,water), a colorant to provide elegance and product distinction. Colormay be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color can be added to Aquacoat® via the use ofalcohol or propylene glycol based color dispersions, milled aluminumlakes and opacifiers such as titanium dioxide by adding color with shearto water soluble polymer solution and then using low shear to theplasticized Aquacoat®. Alternatively, any suitable method of providingcolor to the formulations of the present invention may be used. Suitableingredients for providing color to the formulation when an aqueousdispersion of an acrylic polymer is used include titanium dioxide andcolor pigments, such as iron oxide pigments. The incorporation ofpigments, may, however, increase the retard effect of the coating.

The plasticized aqueous dispersion of hydrophobic controlled releasematerial may be applied onto the substrate comprising thetherapeutically active agent by spraying using any suitable sprayequipment known in the art. In a preferred method, a Wursterfluidized-bed system is used in which an air jet, injected fromunderneath, fluidizes the core material and effects drying while theacrylic polymer coating is sprayed on. A sufficient amount of theaqueous dispersion of hydrophobic material to obtain a predeterminedcontrolled-release of said therapeutically active agent when said coatedsubstrate is exposed to aqueous solutions, e.g. gastric fluid, ispreferably applied, taking into account the physical characteristics ofthe therapeutically active agent, the manner of incorporation of theplasticizer, etc. After coating with the hydrophobic controlled releasematerial, a further overcoat of a film-former, such as Opadry®, isoptionally applied to the beads. This overcoat is provided, if at all,in order to substantially reduce agglomeration of the beads.

Another method of producing controlled release bead formulationssuitable for about 24-hour administration is via powder layering. U.S.Pat. No. 5,411,745, assigned to the Assignee of the present inventionand hereby incorporated by reference in its entirety, teachespreparation of 24-hour morphine formulations prepared via powderlayering techniques utilizing a processing aid consisting essentially ofhydrous lactose impalpable. The powder-layered beads are prepared byspraying an aqueous binder solution onto inert beads to provide a tackysurface, and subsequently spraying a powder that is a homogenous mixtureof morphine sulfate and hydrous lactose impalpable onto the tacky beads.The beads are then dried and coated with a hydrophobic material such asthose described hereinabove to obtain the desired release of drug whenthe final formulation is exposed to environmental fluids. An appropriateamount of the controlled release beads are then, e.g. encapsulated toprovide a final dosage form which provides effective plasmaconcentrations of morphine for about 24 hours.

Controlled Release Osmotic Dosage

Controlled release dosage forms according to the present invention mayalso be prepared as osmotic dosage formulations. The osmotic dosageforms preferably include a bilayer core comprising a drug layer and adelivery or push layer, wherein the bilayer core is surrounded by asemipermeable wall and optionally having at least one passagewaydisposed therein. In certain embodiments, the bilayer core comprises adrug layer with hydrocodone or a salt thereof and a displacement or pushlayer. In certain embodiments the drug layer may also comprise at leastone polymer hydrogel. The polymer hydrogel may have an average molecularweight of between about 500 and about 6,000,000. Examples of polymerhydrogels include but are not limited to a maltodextrin polymercomprising the formula (C₆H₁₂O₅)_(n).H₂O, wherein n is 3 to 7,500, andthe maltodextrin polymer comprises a 500 to 1,250,000 number-averagemolecular weight; a poly(alkylene oxide) represented by, e.g., apoly(ethylene oxide) and a poly(propylene oxide) having a 50,000 to750,000 weight-average molecular weight, and more specificallyrepresented by a poly(ethylene oxide) of at least one of 100,000,200,000, 300,000 or 400,000 weight-average molecular weights; an alkalicarboxyalkylcellulose, wherein the alkali is sodium or potassium, thealkyl is methyl, ethyl, propyl, or butyl of 10,000 to 175,000weight-average molecular weight; and a copolymer of ethylene-acrylicacid, including methacrylic and ethacrylic acid of 10,000 to 500,000number-average molecular weight.

In certain embodiments of the present invention, the delivery or pushlayer comprises an osmopolymer. Examples of an osmopolymer include butare not limited to a member selected from the group consisting of apolyalkylene oxide and a carboxyalkylcellulose. The polyalkylene oxidepossesses a 1,000,000 to 10,000,000 weight-average molecular weight. Thepolyalkylene oxide may be a member selected from the group consisting ofpolymethylene oxide, polyethylene oxide, polypropylene oxide,polyethylene oxide having a 1,000,000 average molecular weight,polyethylene oxide comprising a 5,000,000 average molecular weight,polyethylene oxide comprising a 7,000,000 average molecular weight,cross-linked polymethylene oxide possessing a 1,000,000 averagemolecular weight, and polypropylene oxide of 1,200,000 average molecularweight. Typical osmopolymer carboxyalkylcellulose comprises a memberselected from the group consisting of alkali carboxyalkylcellulose,sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodiumcarboxyethylcellulose, lithium carboxymethylcellulose, sodiumcarboxyethylcellulose, carboxyalkylhydroxyalkylcellulose,carboxymethylhydroxyethyl cellulose, carboxyethylhydroxyethylcelluloseand carboxymethylhydroxypropylcellulose. The osmopolymers used for thedisplacement layer exhibit an osmotic pressure gradient across thesemipermeable wall. The osmopolymers imbibe fluid into dosage form,thereby swelling and expanding as an osmotic hydrogel (also known asosmogel), whereby they push the hydrocodone or pharmaceuticallyacceptable salt thereof from the osmotic dosage form.

The push layer may also include one or more osmotically effectivecompounds also known as osmagents and as osmotically effective solutes.They imbibe an environmental fluid, for example, from thegastrointestinal tract, into dosage form and contribute to the deliverykinetics of the displacement layer. Examples of osmotically activecompounds comprise a member selected from the group consisting ofosmotic salts and osmotic carbohydrates. Examples of specific osmagentsinclude but are not limited to sodium chloride, potassium chloride,magnesium sulfate, lithium phosphate, lithium chloride, sodiumphosphate, potassium sulfate, sodium sulfate, potassium phosphate,glucose, fructose and maltose.

The push layer may optionally include a hydroxypropylalkylcelluloserepresented by a member selected from the group consisting ofhydroxypropylmethylcellulose, hydroxypropylethylcellulose,hydroxypropylisopropylcellulose, hydroxypropylbutylcellulose, andhydroxypropylpentylcellulose.

The push layer optionally may comprise a nontoxic colorant or dye.Examples of colorants or dyes include but are not limited to Food andDrug Administration Colorant (1-D&C), such as FD&C No. 1 blue dye, FD&CNo. 4 red dye, red ferric oxide, yellow ferric oxide, titanium dioxide,carbon black, and indigo.

The push layer may also optionally comprise an antioxidant to inhibitthe oxidation of ingredients. Some examples of antioxidants include butare not limited to a member selected from the group consisting ofascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixtureof 2 and 3 tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene,sodium isoascorbate, dihydroguaretic acid, potassium sorbate, sodiumbisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate,vitamin E, 4-chloro-2,6-ditertiary butylphenol, alphatocopherol, andpropylgallate.

In certain alternative embodiments, the dosage form comprises anhomogenous core comprising hydrocodone or a pharmaceutically acceptablesalt thereof, a pharmaceutically acceptable polymer (e.g., polyethyleneoxide), optionally a disintegrant (e.g., polyvinylpyrrolidone),optionally an absorption enhancer (e.g., a fatty acid, a surfactant, achelating agent, a bile salt, etc.). The homogenous core is surroundedby a semipermeable wall having a passageway (as defined above) for therelease of the hydrocodone or pharmaceutically acceptable salt thereof.

In certain embodiments, the semipermeable wall comprises a memberselected from the group consisting of a cellulose ester polymer, acellulose ether polymer and a cellulose ester-ether polymer.Representative wall polymers comprise a member selected from the groupconsisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tricellulose alkenylates, and mono-, di- andtricellulose alkinylates. The poly(cellulose) used for the presentinvention comprises a number-average molecular weight of 20,000 to7,500,000.

Additional semipermeable polymers for the purpose of this inventioncomprise acetaldehyde dimethycellulose acetate, cellulose acetateethylcarbamate, cellulose acetate methylcarbamate, cellulose diacetate,propylcarbamate, cellulose acetate diethylaminoacetate; semipermeablepolyamide; semipermeable polyurethane; semipermeable sulfonatedpolystyrene; semipermeable cross-linked polymer formed by thecoprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,876;semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat.No. 3,133,132; semipermeable crosslinked polystyrenes; semipermeablecross-linked poly(sodium styrene sulfonate); semipermeable crosslinkedpoly(vinylbenzyltrimethyl ammonium chloride); and semipermeable polymerspossessing a fluid permeability of 2.5×10⁻⁸ to 2.5×10⁻² (cm²/hr·atm)expressed per atmosphere of hydrostatic or osmotic pressure differenceacross the semipermeable wall. Other polymers useful in the presentinvention are known in the art in U.S. Pat. Nos. 3,845,770; 3,916,899and 4,160,020; and in Handbook of Common Polymers, Scott, J. R. and W.J. Roff, 1971, CRC Press, Cleveland, Ohio.

In certain embodiments, preferably the semipermeable wall is nontoxic,inert, and it maintains its physical and chemical integrity during thedispensing life of the drug. In certain embodiments, the dosage formcomprises a binder as described above.

In certain embodiments, the dosage form comprises a lubricant, which maybe used during the manufacture of the dosage form to prevent sticking todie wall or punch faces. Examples of lubricants include but are notlimited to magnesium stearate, sodium stearate, stearic acid, calciumstearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid,sodium stearyl fumarate, and magnesium palmitate.

Coatings

The dosage forms of the present invention may optionally be coated withone or more coatings suitable for the regulation of release or for theprotection of the formulation. In one embodiment, coatings are providedto permit either pH-dependent or pH-independent release, e.g., whenexposed to gastrointestinal fluid. When a pH-independent coating isdesired, the coating is designed to achieve optimal release regardlessof pH-changes in the environmental fluid, e.g., the GI tract. Otherpreferred embodiments include a pH-dependent coating that releases theopioid in desired areas of the gastro-intestinal (GI) tract, e.g., thestomach or small intestine, such that an absorption profile is providedwhich is capable of providing at least about twelve hour and preferablyup to twenty-four hour analgesia to a patient. It is also possible toformulate compositions which release a portion of the dose in onedesired area of the GI tract, e.g., the stomach, and release theremainder of the dose in another area of the GI tract, e.g., the smallintestine.

Formulations according to the invention that utilize pH-dependentcoatings may also impart a repeat-action effect whereby unprotected drugis coated over an enteric coat and is released in the stomach, while theremainder, being protected by the enteric coating, is released furtherdown the gastrointestinal tract. Coatings which are pH-dependent may beused in accordance with the present invention include a controlledrelease material such as, e.g., shellac, cellulose acetate phthalate(CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulosephthalate, and methacrylic acid ester copolymers, zein, and the like.

In another preferred embodiment, the present invention is related to astabilized solid controlled dosage form comprising an opioid coated witha hydrophobic controlled release material selected from (i) analkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof. Thecoating may be applied in the form of an organic or aqueous solution ordispersion.

In certain preferred embodiments, the controlled release coating isderived from an aqueous dispersion of the hydrophobic controlled releasematerial. The coated substrate containing the opioid(s) (e.g., a tabletcore or inert pharmaceutical beads or spheroids) is then cured until anendpoint is reached at which the substrate provides a stabledissolution. The curing endpoint may be determined by comparing thedissolution profile (curve) of the dosage form immediately after curingto the dissolution profile (curve) of the dosage form after exposure toaccelerated storage conditions of, e.g., at least one month at atemperature of 40° C. and a relative humidity of 75%. These formulationsare described in detail in U.S. Pat. Nos. 5,273,760 and 5,286,493,assigned to the Assignee of the present invention and herebyincorporated by reference. Other examples of controlled-releaseformulations and coatings which may be used in accordance with thepresent invention include Assignee's U.S. Pat. Nos. 5,324,351;5,356,467, and 5,472,712, hereby incorporated by reference in theirentirety.

In preferred embodiments, the controlled release coatings include aplasticizer such as those described herein.

In certain embodiments, it is necessary to overcoat the substratecomprising the opioid analgesic with a sufficient amount of the aqueousdispersion of e.g., alkylcellulose or acrylic polymer, to obtain aweight gain level from about 2 to about 50%, e.g., about 2 to about 25%in order to obtain a controlled-release formulation. The overcoat may belesser or greater depending upon the physical properties of thetherapeutically active agent and the desired release rate, the inclusionof plasticizer in the aqueous dispersion and the manner of incorporationof the same, for example.

Alkylcellulose Polymers

Cellulosic materials and polymers, including alkylcelluloses arecontrolled release materials well suited for coating the substrates,e.g., beads, tablets, etc. according to the invention. Simply by way ofexample, one preferred alkylcellulosic polymer is ethylcellulose,although the artisan will appreciate that other cellulose and/oralkylcellulose polymers may be readily employed, singly or on anycombination, as all or part of a hydrophobic coatings according to theinvention.

One commercially-available aqueous dispersion of ethylcellulose isAquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is preparedby dissolving the ethylcellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactantand a stabilizer. After homogenization to generate submicron droplets,the organic solvent is evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it isnecessary to intimately mix the Aquacoat® with a suitable plasticizerprior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during themanufacturing process. A hot melt of a polymer, plasticizer (dibutylsebacate), and stabilizer (oleic acid) is prepared as a homogeneousmixture, which is then diluted with an alkaline solution to obtain anaqueous dispersion which can be applied directly onto substrates.

Acrylic Polymers

In other preferred embodiments of the present invention, the controlledrelease material comprising the controlled-release coating is apharmaceutically acceptable acrylic polymer, including but not limitedto acrylic acid and methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate,poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamidecopolymer, poly(methyl methacrylate), polymethacrylate, poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, poly(methacrylic acid anhydride), and glycidyl methacrylateco-polymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers Ammonio methacrylatecopolymers are well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

In order to obtain a desirable dissolution profile, it may be necessaryto incorporate two or more ammonio methacrylate copolymers havingdiffering physical properties, such as different molar ratios of thequaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Röhm Tech, Inc.There are several different types of Eudragit®. For example, Eudragit Eis an example of a methacrylic acid copolymer which swells and dissolvesin acidic media. Eudragit L is a methacrylic acid copolymer which doesnot swell at about pH<5.7 and is soluble at about pH>6. Eudragit S doesnot swell at about pH<6.5 and is soluble at about pH>7. Eudragit RL andEudragit RS are water swellable, and the amount of water absorbed bythese polymers is pH-dependent, however, dosage forms coated withEudragit RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from RohmPharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D,respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers ofacrylic and methacrylic esters with a low content of quaternary ammoniumgroups, the molar ratio of ammonium groups to the remaining neutral(meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit®RS30D. The mean molecular weight is about 150,000. The code designationsRL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit® RL/RS mixtures areinsoluble in water and in digestive fluids. However, coatings formedfrom the same are swellable and permeable in aqueous solutions anddigestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain acontrolled-release formulation having a desirable dis-solution profile.Desirable controlled-release formulations may be obtained, for instance,from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit®RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Ofcourse, one skilled in the art will recognize that other acrylicpolymers may also be used, such as, for example, Eudragit® L.

Plasticizers

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic controlled release material, theinclusion of an effective amount of a plasticizer in the aqueousdispersion of hydrophobic material will further improve the physicalproperties of the controlled-release coating. For example, becauseethylcellulose has a relatively high glass transition temperature anddoes not form flexible films under normal coating conditions, it ispreferable to incorporate a plasticizer into an ethylcellulose coatingcontaining controlled-release coating before using the same as a coatingmaterial. Generally, the amount of plasticizer included in a coatingsolution is based on the concentration of the film-former, e.g., mostoften from about 1 to about 50 percent by weight of the film-former.Concentration of the plasticizer, however, can only be properlydetermined after careful experimentation with the particular coatingsolution and method of application.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tibutyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

In certain embodiments, the addition of a small amount of talc to thecontrolled release coating reduces the tendency of the aqueousdispersion to stick during processing, and acts as a polishing agent.

The release of the therapeutically active agent from thecontrolled-release formulation of the present invention can be furtherinfluenced, i.e., adjusted to a desired rate, by the addition of one ormore release-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic controlled releasematerial to water soluble material is determined by, among otherfactors, the release rate required and the solubility characteristics ofthe materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

The controlled-release coatings of the present invention can alsoinclude erosion-promoting agents such as starch and gums.

The controlled-release coatings of the present invention can alsoinclude materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain.

The release-modifying agent may also comprise a semi-permeable polymer.In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The controlled-release coatings of the present invention may alsoinclude an exit means comprising at least one passageway, orifice, orthe like. The passageway may be formed by such methods as thosedisclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and4,088,864, all of which are hereby incorporated by reference. Thepassageway can have any shape such as round, triangular, square,elliptical, irregular, etc.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not meant to be construed to limit the claims in anymanner whatsoever.

Example 1

Hydrocodone sustained release tablets were produced with the formula setforth in Table 1A below:

TABLE 1A Amt/unit Amt/batch Ingredient (mg) (gram) HydrocodoneBitartrate 30.0 150.0 Spray Dried Lactose 90.0 450.0 Povidone 8.0 40.0Eudragit RS30D (Solids) 30.0 150.0 Triacetin 6.0 30.0 Stearyl Alcohol50.0 250.0 Talc 4.0 20.0 Magnesium Stearate 2.0 10.0 Opadry RedYS1-15597-A 10.0 50.0 Purified Water * * Total 230.0 1150.0 *Used forprocessing and remains in product as residual moisture only.

According to the following procedure:

-   1. Granulation: Spray the Eudragit/Triacetin dispersion onto the    Hydrocodone Bitartrate,

Spray Dried Lactose and Povidone using a fluid bed granulator.

-   2. Milling: Discharge the granulation and pass through a mill-   3. Waxing: Melt the stearyl alcohol and add to the milled    granulation using a mixer.

Allow to cool.

-   4. Milling: Pass the cooled granulation through a mill-   5. Lubrication: Lubricate the granulation with talc and magnesium    stearate using a mixer.-   6. Compression: Compress the granulation into tablets using a tablet    press-   7. Film Coating: Apply an aqueous film coat to the tablets

The tablets were then tested for dissolution using the followingprocedure:

-   1. Apparatus USP Type I (Basket), 100 rpm.-   2. Medium 700 ml SGF for first 55 minutes, thereafter made 900 ml    with    -   Phosphate Buffer to pH 7.5.-   3. Sampling time 1, 2, 4, 8, and 12 hours.-   4. Analytical High Performance Liquid Chromatography.

The dissolution parameters are set forth in Table 1B below:

TABLE 1B Time % (hour) Dissolved 1 25.5 2 31.7 4 41.5 8 54.7 12 65.0

Example 2

Hydrocodone sustained release tablets were produced with the formula setforth in

Table 2A below:

TABLE 2A Amt/unit Amt/batch Ingredient (mg) (gram) HydrocodoneBitartrate 15.0 187.5 Eudragit RSPO 78.0 975.0 Stearyl Alcohol 27.0337.5 Total 120.0 1500.0

According to the following procedure:

-   1. Milling: Pass stearyl alcohol flakes through a ill.-   2. Blending: Mix Hydrocodone Bitartrate, Eudragit, and milled    Stearyl Alcohol.-   3. Extrusion: Continuously feed the blended material into a twin    screw extruder and collect the resultant strands on a conveyor.-   4. Cooling: Allow the strands to cool a Conveyor.-   5. Pelletizing: Cut the cooled strands into pellets using a    Pelletizer.-   6. Screening: Screen the pellets and collect desired sieve portion.

Dissolution Method:

-   1. Apparatus USP Type I (Basket), 100 rpm.-   2. Medium 700 mL SGF for first hour, thereafter made 900 mL with    Phosphate Buffer to pH 7.5.-   3. Sampling time 1, 2, 4, 8, and 12 hours.-   4. Analytical High Performance Liquid Chromatography.

The dissolution parameters are set forth in Table 2B below:

TABLE 2B Time % Dissolved (hour) SGF/SIF 1 19.5 2 26.3 4 38.2 8 54.0 1263.8

Example 3

Hydrocodone sustained release osmotic tablets are produced with theformula set forth in Table 3A below:

TABLE 3A Ingredient Percentage Drug Layer: Percentage of Drug LayerHydrocodone Bitartrate 25.4 Polyethylene oxide 70.1 Povidone 4 MagnesiumStearate 0.5 Percentage of Displacement Displacement Layer: LayerPolyethylene oxide 68.57 Sodium chloride 26 Hydroxypropylmethylcellulose4.5 Ferric Oxide 0.6 Magnesium Stearate 0.25 BHT 0.08 Percentage ofSemipermeable Wall: Semipermeable Wall Cellulose acetate 95 Polyethyleneglycol 5

The dosage form having the above formulation is prepared according tothe following procedure:

Requisite amounts of hydrocodone bitartrate, of poly(ethylene oxide)possessing a 200,000 average molecular weight, and poly(vinylpyrrolidone) are added to a planetary mixing bowl and are mixed. Then,denatured anhydrous ethyl alcohol is slowly added to the blendedmaterials with continuous mixing for 15 minutes to provide for a wetgranulation. Next, the freshly prepared wet granulation is passedthrough a 20 mesh screen, allowed to dry at room temperature, and passedthrough a 16 mesh screen. Next, the granulation is transferred to aplanetary mixer, mixed and lubricated with the requisite amount ofmagnesium stearate.

A push composition is prepared as follows: first, a binder solution isprepared by dissolving the requisite amount ofhydroxypropylmethylcellulose in of water. Next, butylated hydroxytolueneis dissolved in of denatured anhydrous alcohol. Thehydroxypropylmethylcellulose/water solution is added to the butylatedhydroxytoluene/alcohol solution with continuous mixing. Next, the bindersolution preparation is completed by adding the remaininghydroxypropyl-methylcellulose/water solution to the butylatedhydroxytoluene/alcohol solution, again with continuous mixing.

Next, a requisite amount of sodium chloride is sized using a QuadroComil® mill, used to reduce the particle size of the sodium chloride.The materials are sized with a 21 mesh screen. Next, ferric oxide ispassed through a 40 mesh screen. Then, all the screened materials, ofpharmaceutically acceptable poly(ethylene oxide) comprising a 7,000,000average molecular weight, and hydroxypropylmethylcellulose is added to aGlatt Fluid Bed Granulator bowl. The bowl is attached to the granulatorand the granulation process is initiated for effecting granulation.Then, the binder solution is sprayed onto the powder.

At the end of the solution spraying, the resultant coated granulatedparticles are subjected to a drying process. The coated granules aresized using a Quadro Comil with an 8 mesh screen. The granulation ismixed and lubricated with a requisite amount of magnesium stearate.

Next, the hydrocodone bitartrate drug composition and the pushcomposition is compressed into bilayer tablets on the Kilian® TabletPress. First, the hydrocodone bitartrate composition is added to the diecavity and pre-compressed, then, the push composition is added and thelayers are pressed to a bilayered arrangement.

The bilayered arrangement is coated with a semi-permeable wall. The wallforming composition comprises 95% cellulose acetate having a 39.8%acetyl content, and 5% polyethylene glycol. The wall-forming compositionis dissolved in an acetone:water (95:5 wt:wt) cosolvent to make a 4%solids solution. The wall-forming composition is sprayed onto and aroundthe bilayers in a 24″ Vector Hi® Coater.

Next, two 30 mil (0.762 mm) exit passageways are drilled through thesemi-permeable wall to connect the drug layer with the exterior of thedosage system. The residual solvent is removed by drying for 48 hours at50° C. and 50% humidity. Next, the osmotic dosage forms are dried for 4hours at 50° C. to remove excess moisture.

Many other variations of the present invention will be apparent to thoseskilled in the art and are meant to be within the scope of the claimsappended hereto.

1-38. (canceled)
 39. A solid oral controlled-release dosage form ofhydrocodone, the dosage form comprising a matrix comprising hydrocodoneor a pharmaceutically acceptable salt thereof and a wax, such that thedosage form provides a ratio of a plasma concentration of hydrocodone atthe end of a dosing interval to a maximum plasma concentration ofhydrocodone during the dosing interval of from 0.55 to 1 and effectivepain relief over a period of time of about 12 hours or longer afteradministration to a human patient, wherein the dosage form is a tablet,and the hydrocodone or pharmaceutically acceptable salt thereof is theonly active agent in the dosage form.
 40. The dosage form of claim 39,wherein the effective pain relief is provided for about 12 hours. 41.The dosage form of claim 40, wherein said administration is firstadministration.
 42. The dosage form of claim 41, wherein the wax is afatty acid glyceride.
 43. A solid oral controlled-release dosage form ofhydrocodone, the dosage form comprising a matrix comprising hydrocodoneor a pharmaceutically acceptable salt thereof and a wax, such that thedosage form provides a W₅₀ of hydrocodone of between 4 and 22 hours anda plasma concentration of hydrocodone within a therapeutic range over aperiod of time of about 12 hours or longer after administration to ahuman patient, wherein the dosage form is a tablet, and the hydrocodoneor pharmaceutically acceptable salt thereof is the only active agent inthe dosage form.
 44. The dosage form of claim 43, wherein the dosageform provides the plasma concentration of hydrocodone within thetherapeutic range over a period of time of about 12 hours afteradministration to the human patient.
 45. The dosage form of claim 44,wherein said administration is first administration.
 46. The dosage formof claim 43, wherein said administration is first administration. 47.The dosage form of claim 43, wherein the wax is a fatty acid glyceride.48. The dosage form of claim 43, wherein the dosage form provides aC₂₄/C_(max) hydrocodone ratio of from 0.55 to 1 after saidadministration.
 49. A solid oral controlled-release dosage form ofhydrocodone, the dosage form comprising a matrix comprising hydrocodoneor a pharmaceutically acceptable salt thereof and a wax, such that thedosage form provides a T_(max) of hydrocodone of from about 4 to about14 hours and a plasma concentration of hydrocodone within a therapeuticrange over a period of time of about 12 hours or longer afteradministration to a human patient, wherein the dosage form is a tablet,and the hydrocodone or a pharmaceutically acceptable salt thereof is theonly active agent in the dosage form.
 50. The dosage form of claim 49,wherein the dosage form provides the plasma concentration of hydrocodonewithin the therapeutic range over a period of time of about 12 hoursafter administration to the human patient.
 51. The dosage form of claim50, wherein said administration is first administration.
 52. The dosageform of claim 49, wherein said administration is first administration.53. The dosage form of claim 39, wherein the dosage form provides a meanC₂₄/C_(max) hydrocodone ratio of from 0.55 to 1 after administration toa patient population and the dosing interval is 24 hours.
 54. The dosageform of claim 39, wherein the dosage form provides a C₂₄/C_(max)hydrocodone ratio of from 0.55 to 1 after administration to the humanpatient and the dosing interval is 24 hours.
 55. The dosage form ofclaim 49, wherein the wax is a fatty acid glyceride.
 56. A solid oralcontrolled-release dosage form of hydrocodone, the dosage formcomprising a matrix comprising hydrocodone bitartrate and a wax, suchthat the dosage form provides a plasma concentration of hydrocodonewithin a therapeutic range over a period of time of about 12 hours orlonger after administration to a human patient, wherein the dosage formis a tablet, and the hydrocodone bitartrate is the only active agent inthe dosage form.
 57. The dosage form of claim 56, wherein the wax is afatty acid glyceride.
 58. The dosage form of claim 56, wherein theamount of the hydrocodone bitartrate in the dosage form is equivalent tofrom about 5 mg to about 60 mg hydrocodone.
 59. The dosage form of claim56, wherein the dosage form provides a mean C₂₄/C_(max) hydrocodoneratio of from 0.55 to 1 after administration to a patient population.60. The dosage form of claim 39, which comprises from about 5 to about60 mg hydrocodone.
 61. The dosage form of claim 56, wherein the dosageform provides an in-vitro release of hydrocodone when measured by theUSP Basket method at 100 rpm in 700 ml aqueous buffer at a pH of 1.2 at37° C. of from 10% to about 45% by weight hydrocodone released at 1hour.
 62. The dosage form of claim 56, wherein the dosage form providesthe plasma concentration of hydrocodone within the therapeutic rangeover a period of time of about 12 hours after administration to thehuman patient.
 63. The dosage form of claim 62, wherein saidadministration is first administration.
 64. The dosage form of claim 56,wherein said administration is first administration.
 65. The dosage formof claim 39, wherein the dosage form comprises a lubricant.
 66. Thedosage form of claim 39, wherein the dosage form provides a mean ratioof mean plasma concentrations of hydrocodone at the end of a dosinginterval to mean maximum plasma concentrations of hydrocodone during thedosing interval of 0.55 to 1 after administration to a patientpopulation.
 67. The dosage form of claim 66, which provides aC₂₄/C_(max) hydrocodone ratio of from 0.55 to 1 after saidadministration and the dosing interval is 24 hours.
 68. The dosage formof claim 56, wherein the dosage form comprises a lubricant.